S.-D. Cho et al. / Tetrahedron Letters 44 (2003) 8995–8998
8997
6. Cho, S.-D.; Choi, W.-Y.; Yoon, Y.-J. J. Heterocyclic
Chem. 1996, 33, 1579.
7. (a) Bryant, R. D.; Kunng, F.-A.; South, M. S. J. Hetero-
cyclic Chem. 1995, 32, 1473; (b) Park, J. W.; Kweon, D.
H.; Kang, Y. J.; Lee, W. S.; Cho, S. D.; Yoon, Y.-J. J.
Heterocylic Chem. 2000, 37, 5.
8. Typical experimental procedure of cyclization:
Method A—To a 100 mL flask equipped with a magnetic
stirrer was added N-substituted 2-chloroacetamide 1g
(28.5 mmol), 4-chloro-5-hydroxypyridazin-3-one 2 (31.3
mmol), and Cs2CO3 (65.5 mmol) in acetonitrile (200 mL).
The mixture was refluxed for 43 h, the solvent was
removed under reduced pressure, and CH2Cl2/H2O was
added to the residue. After separating the organic layer,
the aqueous layer was also extracted with CH2Cl2. The
combined organic layer was dried over anhydrous
MgSO4 and evaporated in vacuo. The crude product was
purified by flash column chromatography using EtOAc/
n-hexane (1:2, v/v) as eluent to afford only 3g in 59%
yields.
Scheme 2.
In summary, our method of obtaining pyridazino[4,5-
b][1,4]oxazin-3,8-diones 3 via Smiles rearrangement is
convenient and practical. Our approach using Smiles
rearrangement may also be very useful for the synthesis
of heterocycle fused-[1,4]oxazine such as pyrido[2,3-
b][1,4]oxazine. Further work including the application,
chemical transformation, and biological activity is
under way in our laboratory.
Method B—To a 100 mL flask equipped with a magnetic
stirrer was added N-substituted 2-hydroxyacetamides 5g
(11.4 mmol), 2-tetrahydropyranylpyridazin-3-one 6 (12.0
mmol), and K2CO3 (25.1 mmol) in DMF (60 mL). The
mixture was stirred for 2 h, the solvent was removed
under reduced pressure, and CH2Cl2/H2O was added to
the residue. After separating the organic layer, the
aqueous layer was extracted with CH2Cl2. The combined
organic layer was dried over anhydrous MgSO4 and
evaporated in vacuo. The crude product was purified by
flash column chromatography using EtOAc/n-hexane
(1:2, v/v) as eluent to afford only 7g in 95% yields. And
then, a mixture of isolated N-substituted 2-[5-chloro-6-
oxo-1-(tetrahydropyran-2-yl)-1,6-dihydropyridazin-4-yl-
oxy]acetamide 7g (10.0 mmol) and Cs2CO3 (11.0 mmol)
in acetonitrile (30 mL) was refluxed for 2 h. After stirring
for 30 min at room temperature, the mixture was filtered
to give residue. The residue was poured into
dichloromethane (80 mL), and the organic layer was
washed with water (50 mL). The organic layer was dried
over anhydrous MgSO4. The solvent was removed under
reduced pressure, the crude 3g was purified by silica gel
column chromatography using EtOAc/n-hexane (1:3, v/v)
as eluent to afford only 3g in 96% yields.; 7g: mp
149–150°C; IR (KBr) 3375, 3068, 2940, 1665, 1609, 1516,
Acknowledgements
This work was supported by Korea Research Founda-
tion Grant (KRF-2002-C00008).
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1
1091 cm−1; H NMR (300 MHz, CDCl3) l 7.79 (s, 1H),
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6.73–6.82 (m, 3H), 6.63 (bs, D2O exch., 1H), 6.06 (dd,
J=1.72, 10.26 Hz, 1H), 4.66 (s, 2H), 4.11 (d, J=6.4 Hz,
1H), 3.87 (s, 3H), 3.75 (s, 3H), 3.62–3.64 (q, J=6.5 Hz,
2H), 2.81–2.85 (t, J=6.7 Hz, 2H), 1.21–2.18 (m, 7H); 13C
NMR (CDCl3) l 165.78, 157.82, 152.53, 149.12, 130.29,
126.82, 120.63, 111.48, 111.22, 83.90, 68.88, 68.31, 55.87,
55.80, 40.23, 34.89, 28.85, 27.77, 22.66; (m/z) 452. Anal.
calcd for C21H26ClN3O6 (451.91): C, 55.81; H, 5.80; N,
9.30. Found: C, 55.78; H, 5.77; N, 9.28; 3g: mp 134–
135°C; IR (KBr) 3015, 2978, 2935, 1700, 1639, 1020 cm−1
;
1H NMR (300 MHz, CDCl3) l 7.75 (s, 1H), 6.70–6.81
(m, 3H), 6.09 (dd, J=2.44, 10.82 Hz, 1H), 4.76 (s, 2H),
4.30–4.39 (m, 1H), 4.11 (m, 1H), 4.04 (m, 2H), 3.86 (s,
3H), 3.77 (s, 3H), 2.88 (t, J=6.5 Hz, 2H), 1.18–2.17 (m,
6H); 13C NMR (CDCl3) l 161.76, 154.95, 149.06, 148.05,
136.83, 129.09, 127.20, 124.74, 120.70, 111.63, 82.74,
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